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Dissertations / Theses on the topic 'Cisplatin Biochemistry'

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Published: 4 June 2021
Last updated: 1 February 2022

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1

Holding, Jeremy David. "Cisplatin : protein binding and biological activity." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257185.

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2

Fisher, Joshua. "In Vitro Binding Kinetics of ChemoFilter with Cisplatin." Thesis, University of California, San Francisco, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10165379.

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Introduction: Endovascular chemotherapy treatment allows localized delivery adjacent to the target tumor; allowing an increased dosage and decreased leakage to other areas. It also allows for the opportunity to filter chemotherapy escaping the target tumor and entering the bloodstream. The ChemoFilter - a temporarily deployable, endovascular device will do just that; reducing systemic toxicity thus reducing adverse side effects from chemotherapy treatment. This will allow further increased dosage, increased tumor suppression, and increased tolerance to treatment. ChemoFilter has successfully filtered the chemotherapeutic Doxorubicin, but had yet to be tested in other chemotherapeutics. This study evaluates binding with new chemotherapeutics: Cisplatin, Carboplatin, and a cocktail comprised of Cisplatin and Doxorubicin.

Materials and Methods: ChemoFilter prototypes based on: 1.) Genomic DNA and 2.) Dowex (ion-exchange) resin, were evaluated for their ability to bind chemotherapy in vitro in phosphate-buffered saline (PBS). ChemoFilter was tested free in solution and encapsulated in nylon or polyester mesh packets of various dimensions. Concentrations were quantified using inductively coupled plasma mass spectrometry (IPC-MS), ultraviolet-visible spectrophotometry (UV-Vis), or fluorospectrometry. 11C, 13C, and/or 14C radiolabeling Carboplatin began for in vitro and in vivo ChemoFilter quantification. In vitro quantification can include scintillation and/or gamma counting. In vivo may include Positron Emission Tomography (PET) imaging, Hyperpolarized 13C Magnetic Resonance Imaging (MRI), and/or Magnetic Resonance Spectroscopy (MRS) for real-time visualization. Reactions were verified using High Performance Liquid Chromatography (HPLC) for chemical species identification.

Results and Discussion: Results indicate significant and nearly complete, ~99% (p<0.01) clearance of Cisplatin using the DNA ChemoFilter sequestered in Nylon mesh, quantified with gold standard ICP-MS (evidenced at 214 and 265 nm). The Ion-exchange ChemoFilter has significant clearance, within seconds, of both Doxorubicin and Cisplatin mixed in a cocktail solution. However, it appears some Cisplatin is binding to the Nylon Mesh itself. Size, shape, and material of the mesh have been optimized. A potential mechanism for 11C, 13C, or 14C radiolabeling of Carboplatin has been developed and early results have been successful. ChemoFilter works much more efficiently when sequestered in nylon packets of specific geometries. Significant improvements have been made to ChemoFilter, moving the device closer to clinical trials.

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3

Filipski, Kelly K. "Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity." View the abstract Download the full-text PDF version, 2009. http://etd.utmem.edu/ABSTRACTS/2009-022-Filipski-index.htm.

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Thesis (Ph.D.)--University of Tennessee Health Science Center, 2009.
Title from title page screen (viewed on August 6, 2009). Research advisor: Alex Sparreboom, Ph.D. Document formatted into pages (ix, 79 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 74-78).
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4

Smith, Adam C. R. "The Effects of Carrier Ligands on Cisplatin Binding to Cysteine and Methionine." TopSCHOLAR®, 2017. http://digitalcommons.wku.edu/theses/1969.

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We have reacted several derivatives of the anticancer drug cisplatin with N-acetyl-Lcysteine (N-AcCys) and N-acetyl-L-methionine (N-AcMet), which are two of the primary amino acid targets of platinum. NMR spectroscopy was used to monitor the reactions and determine the effect the different ligands would have on the platinum reactivity. Several of the platinum compounds were tested at pH of 4 and 7, and with platinum:amino acid ratios of 1:1, 2:1 and 1:2. Competition reactions between cysteine and methionine were done to confirm which would react with the platinum compound first. [Pt(dien)(NO3)]+ reacts faster with methionine than with cysteine at both pH 4 and 7 at a 1:1:1 ratio. [Pt(N,N,N',N',N"-pentamethyldiethylenetriamine)(NO3)]+ reacts with methionine faster at pH 4 but with cysteine faster at pH 7. This is most likely due to the thiol in the cysteine starting to deprotonate around pH 7. [Pt(Me4en)(NO3)2] (Me4en = N,N,N',N'-tetramethylethylenediamine) forms several products with N-AcCys at both pH 4 and 7, with the amounts of the products varying depending on the ratio of platinum and Cys. Mass spectrometry indicated one product as {[Pt(Me4en)(H2O)]2(N-AcCys)}2+, with two platinum compounds coordinated to a single cysteine. Lastly Pt[(en)(NO3)2] when reacting with N-AcCys at a ratio of 1:1 will coordinate with 2 different Cys molecules. With an excess of Pt the complex prefers to bind to only 1 Cys.
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5

Dangeti, Venkata Srinivas Mohan Nimai. "Processing of Cisplatin Interstrand crosslinks (ICLs) by DNA repair proteins." University of Toledo Health Science Campus / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1352833172.

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6

Hira, Akshay. "TIP60 regulation of DNp63a is associated with cisplatin resistance." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1566585763492406.

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7

Tacka, Kirk A. Dabrowiak James C. "I. Kinetic study of the reactions of glutathione and thiol drugs with cyclophosphamide. II. Quanitative studies of cisplatin-induced cell death." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2004. http://wwwlib.umi.com/cr/syr/main.

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8

Hostetter, Alethia A. 1981. "In vitro and in cellulo interactions of platinum and ruthenium anticancer metallodrugs with RNA." Thesis, University of Oregon, 2011. http://hdl.handle.net/1794/11254.

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xviii, 125 p. : ill. (some col.)
Since its approval by the FDA in 1978 cisplatin (cis-diamminedichloroplatinum(II)) has revolutionized the treatment of several cancer types, particularly testicular cancer which now has a cure rate greater than 90%. Following the example set by its success, a broad range of antitumor metallodrugs is being developed. One of the most promising of these drugs, currently in Phase Two of clinical trials, is the Ru-based NAMI-A (imadozolium trans -[tetrachloro(dimethylsulfoxide)(imidazole)ruthenate(III)]) which displays low systemic toxicity and strong antimetastatic activity. The majority of anticancer metallodrugs (including NAMI-A and cisplatin) can bind to DNA, which, in many cases, is an important therapeutic target. Much effort has gone into characterizing the DNA binding properties of anticancer metallodrugs. Less study has gone into characterizing the interaction of anticancer mellodrugs with RNA even though RNA is chemically similar to DNA and plays important roles in gene expression and regulation. Focusing on the extensively studied cisplatin, Chapter I covers both what is known about anticancer metallodrug-RNA binding and the information that can be gleaned from DNA binding and drug localization studies. Chapter II provides the details of a kinetic investigation of the in vitro binding of aquated cisplatin to an RNA sequence containing an internal loop derived from the core of the spliceosome, a related RNA hairpin, and the slower reacting DNA hairpin analog. Chapter III follows in cellulo studies with cisplatin-treated S. cerevisiae that demonstrate, using ICP-MS, differences in Pt accumulation in mRNA and rRNA. The effects of cisplatin treatment on S. cerevisiae cell growth and viability were investigated using clonogenic and morphologic assays. In Chapter IV the same protocols were applied in order to investigate Ru accumulation on RNA following S. cerevisiae treatment with NAMI-A. These in cellulo experiments were followed by in vitro binding studies that utilized MALDI-MS to compare Ru interactions with RNA and DNA oligonucleotides following treatment with NAMI-A under different solution conditions, finding enhanced binding in an acidic, reducing environment like that found in tumor tissue. Chapter V pulls together the knowledge gained so far and discusses questions for future investigation. This dissertation includes both previously published and unpublished coauthored material.
Committee in charge: David Tyler, Chairperson; Victoria DeRose, Advisor; Darren Johnson, Member; Andy Berglund, Member; Alice Barkan, Outside Member
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9

Hodzic, Denis. "Effects of EF-24 and Cisplatin on Cancer, Renal, and Auditory Cells." TopSCHOLAR®, 2019. https://digitalcommons.wku.edu/theses/3110.

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Cisplatin is a chemotherapy drug effective against several forms of cancer, but can also cause serious side-effects, including nephrotoxicity and ototoxicity. Curcumin, a natural plant compound, can increase cisplatin’s anti-cancer activity and counteract cisplatin’s deleterious effect on the auditory and renal systems. Unfortunately, curcumin exhibits poor bioavailability, which has promoted interest in the development of synthetic curcumin analogs (curcuminoids) that are soluble, target cancer, and do not cause side effects. This study investigated whether the curcuminoid (3E,5E)-3,5-bis[(2-fluorophenyl) methylene]-4-piperidinone (EF-24) increases the anti-cancer effects of cisplatin against a human ovarian cancer cell line (A2780) and its cisplatin-resistant counterpart (A2780cis), while preventing cisplatin-mediated side effects in a human kidney cell line (HEK-293T) and a mouse auditory hybridoma cell line (HEI-OC1). The effect of cisplatin and EF-24 on cellular viability was measured using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. The expression and activity of signal transduction proteins in several apoptotic pathways was measured using caspase luminescence assays. Reactive oxygen species (ROS) production was also measured using flow cytometry. Our data suggest that cisplatin and EF-24 are effective against ovarian cancer cell lines, but both compounds may also have adverse effects on auditory and renal cells. This project provides relevant information that may improve our understanding of how these compounds function in different tissues, facilitating improved cancer treatment and circumvention of side effects commonly associated with cisplatin treatment.
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10

Sawant, Akshada S. "The Role of Base Excision Repair and Mismatch Repair Proteins in the Processing of Cisplatin Interstrand Cross-Links." University of Toledo Health Science Campus / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1404407224.

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11

Lutterman, Daniel Aaron. "Investigation of transition metal complexes with potential photochemical applications." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1184601514.

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12

Chapman, Erich G. 1984. "Platinum coordination to RNA." Thesis, University of Oregon, 2010. http://hdl.handle.net/1794/11072.

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xix, 111 p. : ill. (some col.)
Since discovery of its biological effects in the late 1960's, cisplatin (cis-diamminedichloroplatinum( II)) has become one of the most broadly-prescribed cancer drugs in use today. A majority of efforts to understand the metallobiochemistry of this drug have focused on describing the interactions of cisplatin-derived Pt(II) complexes with DNA. Drug binding to this "high value" cellular target is believed to trigger the apoptotic pathways that underlie cisplatin's cytotoxic effects. Although RNA is chemically similar to DNA and responsible for accurately transferring, regulating, and transforming the same genetic information that is stored within the DNA genome, surprisingly little is known about platinum(II) drug binding to RNA. Accordingly, the first three chapters of this dissertation describe efforts to address questions regarding cisplatin coordination to RNA on the molecular scale. Chapter I reviews fundamental aspects of how metal complexes interact with nucleic acids, highlighting the bioinorganic chemistry of platinum(II) antitumor drugs. This chapter also introduces the idea that drug binding to RNA may form an important part of how these complexes work in the cell. Chapter II describes cisplatin crosslinking between RNA nucleobases located on opposite sides of the internal loop of an RNA subdomain derived from the catalytic core of the spliceosome. Chapter III describes how platinum adducts disrupt the activity of RNA processing enzymes similar to those that are necessary for maturation, maintenance and recycling of the transcriptome. Chapter III also describes the reversal of RNA platination using thiourea. The chemistry of platinum(II) is also characterized by preferential coordination to sulfur ligands, or thiophilicity. Incorporating this property into RNA chemistry, Chapters IV and V describe the reaction of platinum(II) complexes with phosphorothioate-substituted RNAs. Chapter IV describes engineering platinum(II) crosslinks in the Hammerhead ribozyme through the targeting of a platinum(II) complex to a specific phosphorothioate substitution installed in the active site of this catalytic RNA. Chapter V outlines efforts to characterize the cleavage and isomerization reactions promoted by platinum(II) coordination to phosphorothioate-substituted RNAs. Finally, Chapter VI summarizes the insights gained throughout the course of our studies and provides an outlook on the future of platinum-RNA chemistry. This dissertation includes co-authored material and previously published results.
Committee in charge: Michael M. Haley, Chair; Victoria J. DeRose, Advisor; David R. Tyler; Andrew J. Berglund; Eric A. Johnson
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13

Nielsen, Frederick A. "Harnessing Macrophage Polarization for Platinum-based Immunochemotherapy." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1525778398029577.

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14

Liu, Renyan. "Synergistic growth inhibition and enhancement of cell death by combination of Melanoma Differentiation Associated gene-7 (MDA-7/IL-24) and cisplatin in ovarian cancer cell lines." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/7.

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Ovarian cancer is the most lethal gynecological malignancy among women. The current first-line treatments for ovarian cancer are cisplatin, carboplatin and paclitaxel. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Therefore, the resistance to cisplatin therapy has been a critical hurdle in the management of recurrent ovarian cancer. The mechanisms responsible for cisplatin resistance are not completely understood. In the search for new therapies to overcome/bypass cisplatin resistance, melanoma differentiation gene-7 (MDA-7) IL-24, which is a new cytokine, has anti-cancer efficacy by suppressing cell growth and inducing apoptosis in a broad range of tumor cells and does not induce any toxicity in normal cells, thus, making it a potentially effective therapeutic gene for ovarian cancer. The purpose of this study was to evaluate the potential therapeutic efficacy of MDA-7 to treat ovarian carcinoma. Since adenoviral-mediated MDA-7 gene therapy has been shown to be well tolerated and showed biological activity in clinical studies in the context of other carcinomas we assessed the anticancer effects of Ad.mda-7 and in combination with cis-platinum on ovarian cancer cells. Our results show that the purified recombinant MDA-7 protein, GST-MDA-7, and Ad.mda7 virus (5) induced growth arresst and apoptosis in ovarian cancer cells. However, the apoptosis induction was low and directly correlated with infectivity of Ad.mda-7 virus (5). The use of a modified Ad.mda-7 virus type5, Ad.mda-7 virus type(5/3), inhanced infectivity and significantly enhanced ovarian cancer cell killing in human ovarian cancer cell lines in vitro compared to unmodified Ad.mda-7 virus, Ad.mda-7 virus type5. Also Ad-mda7 synergizes with cis-platinum in vitro and enhances ovarian cancer cell death. Taken together, these findings demonstrate that MDA-7 is capable of promoting growth suppression and inducing cell death in ovarian cancer cells, at least OVCAR cells and support the pharmacological interest of the combination of MDA-7 and cis-platinum.
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15

Puckett, Nathan. "Effects of Binding Affinity between Bovine Serum Albumin and Platinum Drugs." TopSCHOLAR®, 2017. http://digitalcommons.wku.edu/theses/1977.

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Platinum complex drugs such as cisplatin have been used as highly successful chemotherapy drugs since the 1970s. We are interested in how the ligands attached to cisplatin analogs influences their reactivity with biologically relevant targets along with time and amount. For this study, reactions were conducted to determine the reactivity between different platinum compounds and the protein bovine serum albumin. Various platinum compounds with different ligands were reacted in varying amounts with albumin in ammonium acetate buffer for either 1 hour, 4 hours, or 24 hours. Each reaction was quenched after the designated reaction time by dialysis and the platinum bound to the protein was determined by use of ICP. LC-MS was used to find exact peptide residues platinum complexes prefer to bind with but was found to be ineffective. Results show that time has a more significant affect on binding over amount of platinum present. In respect to changing the leaving or carrier ligands on the platinum complex, these changes on the complex did not affect binding significantly with bovine serum albumin. Triamine platinum complexes also seem to bind significantly more than diamine platinum complexes along with anionic form platinum complexes binding significantly better than the cationic form platinum complexes.
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16

Fourrier-Bauchet, Laurence. "Mécanisme d'action de la drogue anticancéreuse cis-dichlorodiammineplatine (II) : étude de l'interaction entre les protéines de réparation des mésappariements et l'ADN platiné." Phd thesis, Université d'Orléans, 2003. http://tel.archives-ouvertes.fr/tel-00483029.

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Le système de réparation des mésappariements de l'ADN (MMR) est impliqué dans la cytotoxicité du cisplatine, puissante drogue anticancéreuse qui interagit avec l'ADN. Nous avons étudié in vitro certaines étapes clé des mécanismes moléculaires qui relient le fonctionnement du système de réparation MMR avec la cytotoxicité de cette drogue. Notre étude s'est focalisée sur l'interaction entre l'ADN platiné et la protéine MutS du système MMR impliquée dans les étapes d'initiation de la réparation. Trois points ont été abordés dans cette étude : i) la reconnaissance par MutS des lésions du cisplatin et des composés de lésion du cisplatine (formés lorsqu'une base non complémentaire est incorporée en face de l'une des deux purines pontées par le platine) ii) l'étape d'initiation de la réparation régulée par la fixation d'ATP et d'ADP par la protéine MutS iii) l'étude d'un dérivé du cisplatine (DACH-platine) ne présentant pas de résistance croisée avec le cisplatine. Les principaux résultats ont été obtenus par des techniques électrophorétiques et par résonance plasmonique de surface. Notre étude montre que MutS joue le rôle d'un senseur des lésions du cisplatine et que l'ADN platiné peut jouer le rôle d'un cofacteur dans la régulation biochimique de l'activité de MutS en présence de nucléotides régulateurs. Nos résultats suggèrent que les composés de lésion des adduits majoritaires du cisplatine pourraient être les lésions critiques impliquées dans la cytotoxicité du cisplatine via le système MMR.
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17

Michels, Judith. "Les Inhibiteurs de PARP dans le Traitement des Cancers Chimio-Résistants. Etude pré-clinique sur la Dépendance à PARP." Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-01063796.

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Introduction Le cancer bronchique est un problème de santé publique en étant la première cause de décès par cancer dans le monde. Il reste de mauvais pronostic avec une résistance au Cisplatine qui est inéluctable dans l'histoire naturelle de la maladie. Nous nous sommes intéressés à l'association du CDDP aux inhibiteurs de la Poly(ADP-ribose) polymérase. Les inhibiteurs pharmacologiques de PARP sont source d'optimisme en oncologie clinique en monothérapie pour des tumeurs déficientes pour une voie de réparation de l'ADN et en association aux cytotoxiques classiques.Matériel et méthodes Nous avons généré 9 clones résistants au CDDP après culture de la lignée A549 dans des faibles doses de CDDP. Deux inhibiteurs pharmacologiques de PARP, CEP8983 (CEP) et PJ34 (PJ), ainsi que des siRNA spécifiques de PARP1 sont utilisés pour l'inhibition de PARP. L'apoptose est mesurée en cytométrie de flux par l'intermédiaire du potentiel membranaire de la mitochondrie DiOC6(3) et la perméabilisation de la membrane plasmique est évaluée par l'iodide de propidium. Le test de clonogénicité permet d'évaluer la capacité des cellules à échapper à la mort et à former une colonie. L'activité métabolique des cellules est mesurée par la mesure de clivage du sel de tetrazolium WST-1. L'immunofluorescence sur cellules fixées a permis d'étudier les dommages de l'ADN (γH2AX), la voie intrinsèque de l'apoptose (l'activation de la caspase 3 et la libération du cytochrome c) et la recombinaison homologue (BRCA1, RAD51). En Western Blot nous avons mesuré l'expression et l'activité de PARP (PAR) ainsi que l'expression d'acteurs de la réparation par excision de base (BER) (XRCC1 and polymérase β). Nous avons développé une méthode de détection de PAR en immunohistochimie sur des tissus inclus en paraffine. Résultats Nous avons trouvé un effet synergique pour l'association du CDDP aux inhibiteurs de PARP in vitro. De façon inattendue nous avons observé que les clones résistants au CDDP développent une addiction à PARP et sont spécifiquement tués par l'inhibition de PARP contrairement à la lignée parentale. Ces clones exhibent une hyperexpression et une hyperactivité de PARP. La réponse aux inhibiteurs de PARP corrèle plus précisément avec l'activation plutôt qu'avec l'expression de PARP, pointant que PAR est un biomarqueur plus précis que PARP. Nous avons observé que l'hyperactivation de PARP accompagne une résistance induite au CDDP et prédispose à une sensibilité aux inhibiteurs de PARP dans d'autres lignées de cancer bronchique (H460 et H1650), de mésothéliome (P31), de cancer de l'ovaire (TOV112D) et de col (HeLa). Dans des expériences in vivo nous avons noté que dans les xénogreffes obtenues à partir de clones résistants au CDDP, l'expression de PAR est stablement retrouvée en immunohistochimie. Ces tumeurs répondaient à l'inhibition de PARP par le PJ en diminuant l'expression de PAR. Les clones résistants au CDDP sensibilisés aux I PARP ont une recombinaison homologue conservée, cependant ont un déficit dans les étapes terminales du BER.Conclusion Nous avons identifié un effet synergique pour l'association des inhibiteurs de PARP au CDDP de des lignées de cancer bronchique. Nous avons observé une dépendance à PARP dans des lignées de cancer bronchique résistantes au CDDP et déficientes pour l'élongation du BER. Nous postulant que PAR est un biomarqueur spécifique de la réponse aux inhibiteurs de PARP.
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18

Mishra, Akaash K. "Developing small molecule inhibitors targeting Replication Protein A for platinum-based combination therapy." Thesis, 2014. http://hdl.handle.net/1805/6466.

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Indiana University-Purdue University Indianapolis (IUPUI)
All platinum (Pt)-based chemotherapeutics exert their efficacy primarily via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. Repair and tolerance of Pt-DNA lesions by nucleotide excision repair and homologous recombination (HR) can substantially reduce the effectiveness of the Pt therapy. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt treatment and increase clinical efficacy. Replication Protein A (RPA) plays essential roles in both NER and HR, along with its role in DNA replication and DNA damage checkpoint activation. Each of these functions requires RPA binding to single-stranded DNA (ssDNA). We synthesized structural analogs of our previously reported RPA inhibitor TDRL-505, determined the structure activity relationships and evaluated their efficacy in tissue culture models of epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC). These data led us to the identification of TDRL-551, which exhibited a greater than 2-fold increase in in vitro and cellular activity. TDRL-551 showed synergy with Pt in tissue culture models of EOC and in vivo efficacy, as a single agent and in combination with platinum, in a NSCLC xenograft model. These data demonstrate the utility of RPA inhibition in EOC and NSCLC and the potential in developing novel anticancer therapeutics that target RPA-DNA interactions.
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